Alkylamino-4-hydroxy quinoline-3-carboxylic esters



,tions Ser. Nos. 540,495 and 573,469,

United States Patent A'LKYLAMINO- l-HYDROXY 'QUINOLINE- 3-CARBOXYLICESTERS Robert-L. Clark, Woodbridge, Arthur A. Patchett, Cranford, andEdward F. Rogers, ors to -Merck 8; C0.,

of New Jersey No Drawing. Continuation-impart of application Ser. No.

515,757, Dec. 22, 1965. This application Mar. 1, 1967. .Ser. No. 619,546

8 Claims. (Cl. 260-286) Inc, Rahway, N.-.l., a corporation ABSTRACT OFTHE DISCLOSURE Cross-references to related applications This is acontinuation-in-part of our pending applicasaid latter application beinga continuation-in-part of Ser. No. 572,225 which is in turn acontinuation-in-part of Ser. No. 515,757 the latter two now abandoned.

Background of the invention (1) The invention pertains to organicheterocyclic compounds which are esters of quinoline carboxylic acids,andto the method of preparing said esters by ring closure of the anilobtained on reaction of a substituted aniline with adialkylalkoxymethylene malonate.

(-2) The compounds of this invention are novelloweralkyl-4-hydroxy-quiuoline-3-carboxylates having a di-;loweralkylamino radical at one of the 6- and 7-positions,

and a diloweralkylamino or a loweralkyl radical at the other. Suchcompounds are highly potent coccidiostats. The prior art disclosescertain quinoline-6,7-diethers, such as6,7-diloweralkoXy-4-hydr0xy-quinoline-3-carboxylates, as havinganticoccidial .properties in U.S. Patents Nos. 3,267,106 and 3,290,315.

Summary An object of this invention is to provide a 'neW class ofquinoline carboxylates. A further object is to provide a class ofloweralkyl 6,7-disubstituted-4-hydroxyquinoline-3carboxyla'tes morepotent as anticoccidial agents than those previously described. Morespecifically the compounds of the invention are loWeralkyl-6,7-disubstituted-4=hydroxy quinoline 3-carboXylates where the 6- and 7-positionsu'bstituents are loweralkyl of 24 carbons or 'diloweralkylaminoradicals, at least one being diloweralkylamino. Another object isprovision of a chemical synthesis of these substances by heat-inducedcyclization of the and obtained on reaction of a 3,4-disubstitutedaniline with diloweralkyl alkoxymethylene malonate. The inventionrelates further to anticoccidial compositions Middletown, N.J., assign-3,377,352 Patented Apr. 9, 1968 containing such substituted quinolinesas an active ingredient, either alone or together with one or more othercoccidiostats, and to the method of 'tre'ating'coccidiosis with suchcompositions. v w

Description of the invention The novel compounds of this invention maybe represented by the structural formula N I a a .I

where R represents loweralkyl such as methyl, ethyl,

propyl or butyl; I

R and R each represent loweralkyl of 2-4 carbon atoms such as ethyl,n-propyl, isopropyl and n-butyl, or a diloweralkylamino radical such asdimethylamino diethylamino, di-n-propylamino, with the proviso that atleast one of R and R must be dilowera1kylamino.-

The invention also contemplates the quaternary salts obtained onreaction of the quinoline I with a loweralkyl halide. I p

In the preferred compounds of our inventon, R 'is methyl or ethyl, andthe substitution at the 6-7 positions is 6-npropyl-7-diethylamino,6-'n-butyl-7-die'thylamiiio, 6,7-diethylamino, or6-diethylamino-7-n-propyl. It 'is this group of substances thatpossesses the greatest degree and spectrum of anticoccidial activity,although all of the substances represented by Formula I are goodcoccidiostats.

Representative of specific quinoline compounds within the scope of thisinvention are methyl 6-n-propyl-7-diethylamino-4-hydroXy-quinoline-3-carboxylate,

ethyl 6 n propyl-7-diethylamino-4-hydroxy-quinoline 3- carboxylate,

methyl 6 n butylJ-diethylamino-4-hydroxy-quinoline-3- carboxylate,

methyl 6-n-prop-yl-7-dimethylamino-4 hydroxy=quinoline- 3-carboxylate,

methyl 6-n-propyl-7-di-n-propylamino'-4-hydroxy quinoline-3-carboxylate,

methyl 6,7 diethylamino-4-hydroxy-quinoline-3-carboxylate,

propyl 6,7 diethylamino-4-hydroXy-quinoline 3ecarboxylate,

ethyl 6,7-diethylamino-4-hydroxyquinoline-3-carboxylate,

methyl 6-diethylamino-7-n-propyl-4-hydroxy-quinoline 3- carboxylate, and

propyl 6-dimethylamino-7-n-butyl-4-hydroxy-quinoline-3- carboxylate.

The quinolat'es of this invention are synthesized from a 3-R -6-R-aniline having the structural formula II by reacting said aniline witha diloweralkyl loweralkoxymethylene malonate of the structure ROCHC(COOR 2 (III) The immediate reaction product is the anil having thestructure CO R3 Ra R7 NCH In Compounds II, III and IV the symbols R Rand R are as previously defined in Formula I. The anil CompoundIV ischemically defined as loweralkyl oz-carboloweralkoxy-B-(3-R -4-R-anilino)-acrylate. The ester (IV) is then converted to the loweralkyl4hydroxy-6R -7-R quinoline-3-carboxylate by heating at elevatedtemperatures.

The reaction of the amine (II) with the 'malonate ester (III) ispreferably carried out in an inert solvent medium such as in aloweralkanol, e.g. methanol, ethanol or isopropanol, or an ether such asdiethyl ether, dioxane, diethylene glycol, dimethyl ether or ethyleneglycol. Essentially equimolar amounts of the reactant are employedalthough this is not essential and a molar excess of either may be usedif desired. Reaction temperatures of from 40120 C., and preferably70-100" C., are employed for best results. When the reaction isessentially complete the solvent may be removed by known techniques, andthe anil (IV) employed directly without further purification in thering-closure reaction leading to the quinolate (I).

This is eifected by heating at ZOO-300 C., and preferably at about240270 C., for from about 10-30 minutes. Although not necessary, it isdesirable to carry out the reaction in a high-boiling organic solventsuch as dimethylsulfone,. dodecylbenzene, biphenyl, diphenylether andsimilar solvents inert under the reaction conditions. At the end of thereaction period the mixture is cooled and the desired loweralkyl4-hyd-roxy-6,7-disubstituted-quinoline-3-carboxylate recovered andpurified by techniques 'known to those skilled in this art.

It has been found convenient to carry out the complete synthetic processwithout purification of the intermediate anil (IV), and in some caseswithout isolation of the 3-R -4-R -aniline (II). When loweralkyl6-loweralkyl-7-dialkylamino-4-hydroxy-quinoline-3 carboxylates arecontemplated by this invention. These salts are ohby catalytic reductionof the corresponding nitrobenzene in a lower alkanol, and in such caseswe prefer to simply remove the catalyst and treat the alkanolic reactionmixture containing 3-R -4-R -aniline with the alkoxymethylene malonate.

The compounds of Formula 1 above form quaternary salts on heating withloweralkyl halides, and such salts are contemplated by'this invention.These salts are obtained by employing a molar excess of are readilypurified by crystallization from solvents such as acetonitrile. Thequaternary of methyl 6-npropyl-7 diethylamino 4-hydroxy-quinoline 3carboxylate and methyl iodide, named 3-carbomethoxy-4-hydroxy 6 n--propyl-7diethylmethyl-quinolyl ammonium iodide may be picturedstructurally 'as H 03 o 0 0 CH:

N+ \N/ H Gr 311;

Representative examples of other qua-ternary salts" are 3 alkyl halide,and

thoxy-4-hydroxy-7-n-propyl-6-quinolyl diethylmethyl ammonium iodide, and3-carboeth0xy-4-hydroxy-6-triethyl- 7-diethylamino quinolyl ammoniumchloride. These salts are, lik the parent compounds, highly activeanticoccidial agents.

The novel quinoline-3-carboxylates of Formula I above may also beprepared by esterifying the corresponding quinoline-B-carboxylic acid.This process is effected by treatin the free acid with a loweralkanol inthe presence of a mineral acid such as hydrochloric acid, sulphuricacid, and the like. The esterification temperature should be maintainedat about IS- C., conveniently at about 100 C. for several hours. Theacid and excess alkanol may then be removed in vacuo and the residualester (1) isolated and purified by conventional techniques such asneutralization, extraction into and crystallization from organicsolvents.

The compounds of Formula I are also preparable from the correspondingquinoline-S carboxylic acid halide by reaction of an acid halide such asthe acid chloride, with a loweralkanol, e.g. methanol or ethanol, atabout 40- C. The loweralkyl quinolate is isolated and purified bystandard techniques.

The 4-hydroxy-6-R -7-R -quinoline-3-carboxylic acids, Where R and R areas previously defined, referred to hereinabove may be obtained byheating a loweralkyl ester thereof with a base, such as an aqueousalkali metal hydroxide. The corresponding acid halides, such as4-hydroxy-6-R -7-R -quinoline-3-carbonyl chloride or bromide, aresynthesized by reacting the free acid with thionyl chloride or bromideat an elevated temperature of about 6090 C.

Coccidiosis is a widespread poultry disease involving the invasion ofcaecal and intestinal mucosa by coccidia, specifically protozoanparasites of the genus Eimeria. The most important of these species areE. maxima, E. ascervulina, E. tenella, E. necatrix, E. brunetti, E.praecox and E. mitis. Related species of coccidia such as E. meleagridisand E. adenoides cause coccidiosis in turkeys. When left untreated, thesevere forms of the disease leads to poor weight gain, reduced feedefficiency, reduced egg production and high mortality. For thesereasons, the effective control of coccidiosis is highly important to thepoultry industry.

It has been discovered that the loweralkyl 6-R -7-R -4hydroxy-quinoline-3-carboxylates of Formula I above, and the quaternarysalts thereof, are highly effective for the treatment and prevention ofcoccidiosis.

In using the compounds of this invention in the treatment and preventionof coccidiosis, they are conveniently fed to poultry as a component ofthe feed of the animals although they may also be given dissolved orsuspended in the drinking water. According to one aspect of theinvention, novel compositions are provided in which compounds of FormulaI above are present as an active anticoccidial ingredient. Suchcompositions comprise the quinolates intimately dispersed or admixedwith an inert carrier or diluent. By an inert carrier is meant one thatis nonreactive with respect to the quinolate and that may beadministered with safety to the animals. The carrier or diluent ispreferably one that is or may be an ingredient of the animal feed and isusually itself an element of poultry sustenance.

The compositions which are a preferred feature of this aspect of theinvention are the so-called feed supplements in which the activeingredient is present in relatively large amounts and which are suitablefor addition to the poultry feed either directly or after anintermediate dilution or blending step. Examples of carriers or diluentssuitable for such compositions are solid, orally ingestable, nutritivecarriers such as distillers dried grains, corn meal, citrus meal,fermentation residues, ground oyster shells, wheat shorts, molassessolubles, corn cob meal, edible vegetable substances, toasted dehulledsoya flour, soybean mill feed, antibiotic mycelia, soya grits, crushedlimestone and the like. The quinolate is intimately dispersed or admixedthroughout the solid inert carrier by methods such as grinding,stirring, mil-ling or tumbling. By selecting proper diluents and byaltering the ratio of carrier to active ingredient, compositions of anydesired concentration may be prepared. Formulations containing fromabout 1% to about 40% by weight, and preferably from about 2-25% byweight of active ingredient are particularly suitable for addition topoultry feeds, and compositions containing from about 515% by weight ofquinolate are very satisfactory. The active compound is normallydispersed or mixed uniformly in the diluent but in some instances may besorbed on the carrier. The optimal concentration of coccidiostat inthese feed supplements will depend to some extent on the particularcompound employed. Since it is convenient for the feed manufacturer touse about one pound of feed supplement for each ton of finished feed,the preferred concentration of any one of our coccidiostats in a feedsupplement is partly a function of the level of active ingredientdesired in the finished feed.

Examples of typical feed supplements containing a compound of thisinvention dispersed in a solid carrier are:

- 7 Lbs. Methyl 6-n-propyl-7-diethylamino-4-hydroxyquinolate-3-carboxylate 5.0 Wheat shorts 95.0

Ethyl 6 diethylamino 7-n-propyl-4-hydroxy-quinoline-3-carboxylate 10.0Soya grits 90.0

Methyl 6,7-diethylamino-4-hydroxy-quinoline-3-carboxylate 15.0

Corn distillers dried grains 85.0

These and similar feed supplements are prepared by uniformly mixing thequinolate with the carrier or carriers.

The feed supplements of the type illustrated hereinabove are usuallyfurther diluted with materials such as corn meal or soybean meal beforebeing incorporated in the animal feed. In this intermediate processingstep the level of coccidiostat in the carrier is brought down to fromabout 0.1% to about 1.0% by weight. This dilution serves to facilitateuniform distribution of the substance in the finished feed. The finishedfeed is one that contains a source of fat protein, carbohydrate,minerals, vitamins and other nutritional factors.

The amount of loweralkyl 6-R -7-R -4-hydroxy-quinoline-3-carboxylate(where R and R are as previously defined) required for effective controlof coccidiosis will depend upon factors such as the specific compoundemployed, the type and severity of infection, and duration of treatment.In any event, only a minor amount is necessary in relation to the totalfeed or drinking water consumption. Good prophylactic results areachieved when the feed administered to poultry contains from about0.0005% to about 0.05 by weight of our quinolate compounds, andpreferably from about 0.00075% to about 0.0125% by weight. Wit-h thepreferred compounds of the invention excellent results are achieved atdose levels in the lower end of this range. For therapeutic use, higherlevels of up to 0.1% by weight of feed may be used effectively for shortperiods of time.

Administration via the drinking water of the birds is often employed inthe therapeutic use of our compounds since poultry with coccidiosis areapt to consume less solid feed than normal birds. The compounds may beadded directly to the drinking water. Alternatively, water-solublepowders may be prepared, in which the coccidiostat is intimately admixedwith a suitable carrier, such as dextrose or sucrose, and these powdersadded to the drinking water of poultry as necessary. Such water-solublepowders may contain any desired concentration of coccidiostat, v.andpreparations containing from 125% by weight of active compound aresuitable.

Our loweralkyl 6 R -7-R -4-hydroxy-quinoline-3 cmboxylates are activeagainst the important species of coccidia. Their potency against E.tenella and E. bnm'etfi is of particular significance inasmuch as theselead to serious forms of infection.

According to an additional aspect of our invention, there are providedanticoccidial compositions containing a quinolate of Formula I abovetogether with a second coccidiostat such as amprolium, zoalene,nicarbazin and the like. There is evidence that compositions containingboth a quinolate and amprolium afford better control of coccidiosis thanis obtainable with either substance alone. Thus, poultry feedcompositions containing from about 0.001- 0.005 by weight of methyl (orethyl)-6-n-propyl-7-diethylamino 4-hydroxy-quinoline-3-carboxylate andfrom about 0.0050.015% by weight of amprolium afford excellent controlof coccidiosis in poultry. Our feed compositions may also contain othersubstances useful for poultry well-being such as vitamins, antibioticsor growth promotants.

The anticoccidial activity of the loweralkyl 6-R -7-R4-hydroxy-quinoline-3-carboxylates is determined by feeding groups ofstraight run White Leghorn chicks a ration containing gradedconcentrations of quinolate compound and orally inoculating the birdswith sporulated oocysts of the coccidia on the second day of the test.With E. tenella 50,000 oocysts are used, and with E. brzmetti, E. maximaand E. acervsulirm 100,000 oocysts are employed. The birds are fed themedicated diet for a period of days (58), then weighed and sacrificed,and examined for remaining oocysts and/ or lesions due to coccidiosis.(Details of these assays appear in U.S. Patents Nos. 3,020,200 for E.tenella and 3,211,610 for E. brunetti and other species.) The activityof the quinolate is expressed in terms of the weight percentconcentration in the feed that provides the desired control of theinfection. As previously stated, our compounds have significant activityat feed concentration levels of about 0.0005 to about 0.05% by weight,the precise optimum level depending on severity andtype of infection.

The anticoccidial activity of representative compounds of this inventionagainst E. tenella and E. brunetti is as follows:

The assay procedure is found in Example 8 of Patent 3,020,200 andExample 2 of Patent 3,211,610.

In other experiments, the anticoccidial activity is determined by theprocedure of Example 4 of Patent 3,211,610. Methyl-6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3- carboxylate has theactivity set forth below.

8 hours and then concentrated to dryness in vacuo to remove t-he solventand the alcohol formed as a reaction product. The resulting residueconsisting of ethyl Ot-Cafboethoxyfl-(3-diethy1amino-4-n-propyl-anilino) -acrylate Concen- PercentMillions oi tration No. Percent Weight Ooeysts in in Feed ChicksMortality Gain Surviving Birds E. tenella. 0.00075 20 10 79 8. 2 0.001520 105 6. 0

Iniected Control... 120 57 48 20. 0 Normal Control 40 0 100 0. 1 E.mazima 20 0 78 1.6 20 0 85 0. 2

Infected Control 120 0 73 5.3 Normal Control.-. 40 0 94 0. 1 E. bTtmetti0. 0004 10 83 3. 4 0.00075 10 0 8S 3. 7

Infected Control 60 8 43 18. 7 Normal Control 0 109 0. 1

The following examples are given for the purpose of illustration and notby way of limitation.

Example l.-Methyl 6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate 52.3 g. of 2-n-propyl-5-nitro-N,N-diethyl aniline in 500 ml. ofmethanol is hydrogenated in the presence of 3.5 g. of 5% palladium oncarbon catalyst at room temperature and under a positive hydrogenpressure of about 40 p.s.i. When the theoretical amount of hydrogen isabsorbed, the hydrogenation is stopped and the catalyst removed byfiltration. The filtrate is concentrated under reduced pressure to anoil consisting predominantly of 2-n-propy1-5- amino-N,N-diethyl aniline,which product is used directly in the next step without furtherpurification.

To 48.7 g. of the oil obtained as described immediately above there isadded 43.5 g. of dimethyl methoxymethylene malonate in 1 liter oftoluene. The resulting mixture is refluxed for 2 hours and thenconcentrated under reduced pressure to remove the toluene to afford aresidue of 86 g. of the anil methylwcarbomethoxy-fi-B-diethylamino-4-npropylanilino)-acrylate. Thissubstance is used as is Without further purification.

1500 ml. of dodecyl benzene is heated to 250-260 C. with stirring and 86g. of the anil is added over a period of about 5 minutes. The resultingsolution is stirred at 250260 C. for 15-20 minutes and then allowed tocool, with stirring, to room temperature. The resulting solid iscollected by filtration, washed with acetone at room temperature anddried to afford substantially pure methyl 6- n-propyl 7diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 198204 C. Thisproduct is dissolved in 3 volumes of dimethylformamide, treated withactivated carbon, filtered and the filtrate chilled to 05 C. The productcrystallizes and is recovered by filtration, M.P. 212 C.

A second crop is obtained by reheating the dodecyl benzene filtrate at250260 C. for 15 minutes, cooling it to room temperature, and adding 400ml. of acetone. The resulting solid methyl 6n-propyl-7-diethylamino-4-hy droxy-quinoline-3-carboxylate is recoveredand purified in the same manner as stated above.

Example 2.Ethy1 6-n-propyl-7-diethylaminol-hydroxyis added to 400 ml. ofrapidly stirred dodecyl benzene at 250-260 C. The mixture is held atthis temperature for 15 minutes and then allowed to cool to roomtemperature. The resulting solid is removed by filtration and washedwith acetone to give 5 g. of ethyl6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 204-206 C.

When the above process is repeated using 4-n-propyl 3- dimethylaminoaniline as starting material there is obtained ethyl 6n-propy1-7-dimethylarnino-4-hydroxy-quincline-3- carboxylate.

Example 3.-Methyl6-isobutyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate 10 g. of 2isobutyl-S-nitro-N,N-diethyl aniline in 100 ml. of methanol arehydrogenated at room temperature over 0.7 g. of palladium-carboncatalyst under a positive hydrogen pressure of about 40 p.s.i. until thetheoretical amount of hydrogen is absorbed. The catalyst is then removedby filtration and the mixture concentrated in vacuo to an oil of4-isobutyl-3-diethylamino aniline. To this oil there is added 8 g. ofdimethyl methoxymethylene malonate in 200 ml. of toluene. The resultingmixture is refluxexl for 90 minutes and then concentrated to dryness invacuo to afford a residue of methyl a-carbomethoxy-fi-(3-diethylamino-4-isobutyl-anilino -acrylate.

This latter substance is added directly to 300 ml. of dodecyl benzene at250-260 C. The mixture is stirred at that temperature for 20 minutes. Itis then cooled to room temperature and the resulting solid removed byfiltration, washed with acetone and dried to afford methyl 6-isobutyl- 7diethylamino 4 hydroxy quinoline 3-carboxylate, M.P. 206208 C.

Example 4.Methyl 6-sec-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate When the process of Example 3 isrepeated employing as starting material Z-sec-butyl-S-nitro-N,N-diethylaniline, there is obtained methyl 6-sec-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 239243 C.

Example 5.(A) Methyl 6-n-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate 32 g. of 2-n-butyl-5-nitro-N,N-diethylaniline in 300 ml.

of methanol are hydrogenated at room temperature using 2 g. of 5%palladium-on-carbon catalyst and under about 40 p.s.i. of hydrogenpressure. The hydrogenation is al- 5 lowed to proceed until thetheoretical amount of hydrogen is absorbed, and at the end of this timethe catalyst is filtered off. The filtrate is concentrated to dryness toaiTord 30 g. of an oil consisting predominantly of2-nbutyl-5-amino-N,N-diethyl aniline. This material is divided into twoequal portions, one being used in the remainder of this experiment andthe other in the experiment described in part B following.

To 15 g. of the foregoing product there is added 15 g. of dimethylmethoxymethylene malonate in 300 ml. of toluene. This mixture isrefluxed for 2% hours and the toluene then removed by concentration invacuo. The residual anil is not purified further but is added directlyto 500 ml. of dodecyl benzene at 250260 C. The mixture is stirred atthis tempereture for 30 minutes and then cooled slowly to roomtemperature. The solid product is separated by filtration, washed withacetone and dried to afford 5.6 g. of methyl 6-n-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 200205 C.

(B) Ethyl 6-n-butyl-7-diethylamino-4-hydroxyquinoline-3-carboxylate 15g. of the aniline derivative obtained above is reacted with diethylethoxymethylene malonate and the resulting anil heated in dodecylbenzene as previously described to afford 9.3 g. of ethyl6-n-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 198200C.

Example 6.-Methyl 6-isopropyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate 26 g. of 2-isopropyl-5-nitro-N,N-diethylaniline are bydrogenated to 2-isopropyl-5-amino-N,N-diethyl aniline,this latter material reacted with 22 g. of dimethyl methoxymethylenemalonate in 500 ml. of toluene, and the resulting anil heated in 700 ml.of dodecyl benzene, following the procedure of Example 1, to afford 12.3g. of methyl 6 isopropyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 24625 3 C.

When this procedure is repeated employing 2-isopropyl-5-nitro-N,N-di-methyl aniline and diethyl ethoxymethylene malonate,there is obtained ethyl6-isopropyl-7-dimethylamino-41hydroxy-quinoline-3-carboxylate.

Example 7.-(A) Methyl 6-ethyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate 44.4 g. of 2-ethyl-5-nitro-N,N-diethylaniline in 400 ml. of methanol is hydrogenated at room temperature using2 teaspoons of Raney nickel catalyst under about 40 p.s.i. of hydrogenpressure. When hydrogen uptake is complete, the catalyst is filteredofl? and the solution divided into two equal portions. To one portionthere is added 17.4 g. of dimethyl methoxymethylene malonate, and themixture heated for one hour on a steam bath. The reaction mixture isthen evaporated to an oil in vacuo, which oil consists predominantly ofthe anil methyl a-carbomethoxy ,8 (3 diethylamino-4-ethylanilino)-acrylate. This material is added directly to 500 ml. of dodecyl benzeneand the mixture heated at 255 C. for 30 minutes. The resulting solid iscollected by filtration and recrystallized from dimethyl formamide toafford substantially pure methyl6-ethyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, M.P. 244 C.

(B) Ethyl 6-ethyl-7-diethylamino-4-hydroxyquinoline-3-carboxylateExample 8.Methyl 6-diethylamino-7-n-propyl-4-hydroxy-quinoline-3-carboxylate 5 g. of dimethyl methoxymethylenemalonate is added to 5.7 g. of 3-n-propyl-4-diethylamino aniline. Theresulting mixture is heated on a steam bath for 15 hours to 10 producethe anil methyl a-carbomethoxy-fi-(3-n-propyl-4-diethyla-mino-anilino)-acrylate as an oil. This oil is added directlyto 175 ml. of dodecyl benzene at 250 C. The mixture is stirred at thistemperature for 20 minutes and then cooled to room temperature. Thedodecyl benzene is decanted from the dark oil which forms. The oil istriturated with acetone to afford a thin solid which is recrystallizedfrom 3 ml. of dimethylformamide to give methyl6-diethylamino-7-n-propyl-4-hydroxy-quinoline-3- carboxylate, M.P.219-220 C.

When diethyl ethoxymethylene malonate is employed in the above processthere is obtained ethyl6-diethylamino-7-n-propyl-4-hydroxy-quinoline-3-carboxylate.

Example 9.Ethyl 6-dimethylarnino-7-n-propyl-4-hydroxy-quinoline-3-carboxylate 10 g. of 3-n-propyl-4-dimethylaminoaniline is added to 12.7 g. of diethyl ethoxymethylene malonate in 200m1. of toluene. The reaction mixture is refluxed for 2 hours and thesolvents are then removed by concentration in vacuo. The residue of theanil is added directly to 400 ml. of dodecyl benzene which has beenpreviously heated to 250.260 C. This temperature is maintained for 20minutes and the mixture then cooled to room temperature. The solidproduct is removed by filtration and washed with acetone to yield ethyl6-dimethylamino-7-npropyl-4-hydroxy-quinoline 3 carboxylate, M.P. 281-283 C.

Example 10.Methyl 6-dimethylamino-7-n-propyl-4-hydroxy-quinoline-3-carboxylate When the procedure of Example 9 isrepeated using dimethyl methoxymethylene malonate, there is obtainedmethyl 6-dimethylamino-7-n-propyl-4-hydroxy-quinoline- 3carboxylate,M.P. 270-275 C.

Example ll.Methyl 6-diethylamino-7-isopropyl-4-hydroxy-quinoline-3-carboxylate Example 12.Methyl6,7-bis-dimethylamino-4-hydroxy-quinoline-3-carboxylate 12 g. of3,4-bis-dimethylamino nitrobenzene in 100 ml. of methanol ishydrogenated at room temperature using 0.5 g. of palladium-oncharcoalcatalyst under a positive hydrogen pressure. When the desired quantityof hydrogen is absorbed, the catalyst is removed by filtration and 8.5g. of dimethyl methoxymethylene malonate are added to the methanolfiltrate containing 3,4-bis-dilmethylamino aniline. The resultingmixture is heated on a steam bath for 3 hours and the solvent is thenremoved in vacuo to leave the anil methyla-carbomethoxy-B-(3,4-dimethylamino-anilino)-acrylate. This product isadded directly to ml. of dodecyl benzene at 250 C. and the mixture heldat this temperature for 30 minutes. It is then cooled to roomtemperature and the resulting crystalline methyl6,7-bis-dimethylamino-4-hydroxy-quinoline 3 carboxylate is recovered byfiltration, M.P. 273 C.

When the above process is carried out and diethyl ethoxymethylenemalonate is used in place of dimethyl methoxymethylene malonate, ethyl6,7-bis-dimethylamino-4- hydroxy-quinoline-3-carboxylate is obtained,M.P. 275 276 C.

Example 13.Methyl 6,7-bis-diethylamino-4-hydroxyquinoline-3-carboxylateA solution of 21.7 g. of 4-nitro-N,N,N',N'-tetraethy1-o-phenylenediamine in 200 ml. of methanol is hydrogenated using 1teaspoonful of Raney nickel as the catalyst. The calculated hydrogenpressure drop is 72 lbs. and the observed is 61 lbs. after 2 hours atroom temperature. At the end of this time the catalyst is filtered ofifand the filtrate is treated with 17 g. of dimethyl methoxymethylenemalonate. The resulting solution is heated on a steam bath for 1 hourand then evaporated to dryness in vacuo. The residue is taken up in 125ml. of toluene and this solution evaporated to dryness in vacuo, Theresidue is again taken up in 125 ml. of toluene, heated on a steam bathfor 30 minutes and then evaporated to dryness in vacuo. This resultinganil (an oil) is added to 400 ml. of dodecyl benzene at 250 C. Themixture is stirred and heated at 245-250 C. for 30 minutes, and thenallowed to cool to room temperature. A dark gum separates. The motherliquor is decanted and the gum rubbed with ether. The ether is decantedand the gum extracted with warm acetone, this causing the gum tocrystallize. The crystals are collected (M.P. 247 C., dec.), washed withhot ethanol and then recrystallized from dimethylformamide to givesubstantially pure methyl 6,7-bis-diethylarnino-4- hydroxyquinoline-3-carboxylate, M.P. 251 C. (dec.).

When the above reaction is repeated usingN,N-dimethyl-2-diethylamino-S-nitroaniline orN,N-dibutyl-2-diethylamino-S-nitroaniline, there is obtained methyl4-hydroxy- 6-diethylamino-7-dimethylamino-quinoline-3 carboxylate andmethyl 4-hydroxy-6-diethylamino 7 dibutylaminoquinoline-3-carboxylate,respectively.

The ethyl esters of these4-hydroxy-6,7-dialkylaminoquinoline-3-carboxylates are produced in likemanner using diethyl methoxymethylene malonate in the foregoing processinstead of the dimethyl malonate.

Exalmple l4.-Methyl 6-dimethylamino-7-diethylamino-4-hydroxy-quinoline-3-carboxylate A solution of 11.9 g, of1-diethylamino-2-dimethylamino-S-nitrobenzene is hydrogenated in 150 ml.of methanol using 1 teaspoonful of Raney nickel catalyst. When hydrogenabsorption ceases, the catalyst is removed by filtration and themethanol solution mixed directly with 8.5 g. of dimethylmethoxymethylene malonate in 50 ml. of toluene. The mixture is heated ona steam bath for 30 minutes and then evaporated to an oil in vacuo, theoil consisting essentially of the anil of the two reactants. Thisproduct is then added to 200 ml. of dodecyl benzene at 255 C. andmaintained at that temperature for 25 minutes. The reaction mass iscooled to room temperature and the solid methyl6-dimethylamino-7-diethylamino-4-hydroxy-quinoline-S-carboxylaterecovered :by filtration. It is recrystallized from dimethylformamide toafford substantially pure material, M.P. 253 C.

Example 15 .Ethy1 6,7 -bis-diethylamino-4-hydroxyquinoline-3-carboxylateWhen the procedure of Example 14 is repeated using as starting material13.3 g. of 1,Z-bis-diethylamino-4-nitrobenzene, carrying out the Raneynickel reduction in ethanol, and using 13 g. of diethyl ethoxylmethylenemalonate, there is obtained ethyl6,7-bis-diethylamino-4-hydroxyquinoline-3-carboxylate, M.P. 264-265 C.

Example 16.3-carbomethoxy-4-hydroxy-fi-n-propyl- 7-quinolyldiethylmethyl ammonium iodide To 2.5 g. of methyl6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate is added 15ml, of methanol and 25 ml. of methyl iodide. The resulting solution isheated under reflux for days. The solvents are then removed in vacuo andthe residue crystallized from acetonitrile to give 1.05 g. of3-carbometoxy-4-hydroxy-6-npropyl-7-quinolyl diethylmethyl ammoniumiodide. Recrystallization from acetonitrile affords substantially purematerial, M.P. 126-127 C.

Example 17.Methyl 6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate To a suspension of 0.6 g. of6-n-propyl-7-diethylamino- 4-hydroxy-quinoline-3-carboxylic acid in 20ml. of methanol there is added 1.5 ml. of concentrated sulfuric acid.The resulting mixture is heated on a steam bath for 12 15 hours and mostof the alcohol then removed by concentration in vacuo. The residue iscooled, neutralized with 10% sodium carbonate and the resultingprecipitate separated and crystallized from dimethyl formamide to givesubstantially pure methyl 6-n-propy1-7-diethylarnino-4-hydroxy-quinoline-3-canboxylate.

1 g. of 6-n-propy1-7-diethylamino-4-hydroxy-quinoline- 3-carboxylic acidis refluxed in benzene for 7 hours with a molar equivalent of thionylchloride. The resulting acid chloride is separated and refluxed for 5hours in 40 ml. of methanol. The reaction mixture is then filtered, thefiltrate chilled and the solid product separated. It is recrystallizedfrom dimethyl formamide to give methyl 6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate.

The starting materials for preparing the lowera-lkyl 6- loWeralky-l 7dialkylamino 4 hydroxy quinoline- 3-carboxylates of this invention are3-dialkylamino-4- loweralkyl anilines (alternatively named as2-loweralkyl- 5-amino-N,N-dialkylanilines) of the formula Y NH2 where Yis loweralkyl and Y is diloweralkylamino. Such materials are obtained oncatalytic hydrogenation of the corresponding nitro compounds using apalladium or Raney nickel catalyst. Those nitro compounds which are notspecifically described in the literature may be prepared by theprocedures stated below for making the starting compounds of Examples 17above.

(A) A solution of 54 ml. (77 g.) of nitric acid (d. 1.42) in 75 ml. (138g.) of sulfuric acid ((1. 1.84) is added dropwise with vigorous stirringto g. of n-propylbenzene over a period of about 2 hours. During theaddition, the temperature is kept at 2530 C. with external cooling.After the addition is complete, the mixture is stirred for an additional2 hours at 2530 C. and then for 1 hour at 40 C. The mixture is thenpoured onto chopped ice with stirring and extracted with 3 x 75 ml. ofhexane. The hexane extracts are combined, washed successively with .50ml. portions of water, aqueous sodium bicarbonate, and finally withwater again. The hexane solution is dried over magnesium sulfate,filtered and the hexane removed under reduced pressure. The residual oilis distilled under reduced pressure using a spinning band tractionatingcolumn. The desired o-isomer is the lowest boiling isomer. It boils at118 C./l5 mm., and this fraction of the distillate is collected to giveZ-nitro-n-propylbenzene.

Other 2-nitro-alkylbenzenes are prepared in the same manner by nitrationof the appropriate alkyl benzene. Representative examples have thefollowing constants: 2- nitroisobutylbenzene, B.P. 124 C./ 15 mm.;2-nitro-sbutylbenzene, B.P. 122 C./l3 mm.; 2-nitro-n-butylbenzene, B.P.132 C./ 14 mm.; 2-nitro-isopropylbenzene; B.P. C./15 mm.

(B) Z-n-propyl-N,N-diethylaniline.79 g. of 2-nitron-propylbenzene in 600ml. of absolute ethanol and 64 ml. of acetaldehyde is hydrogenated inthe presence of 5 g. of 5% palladium-on-carbon catalyst at roomtemperature and under about 40 psi. hydrogen pressure. After thehydrogen absorption ceases (an amount greater than theory is absorbeddue to the excess acetaldehyde present) the catalyst is removed byfiltration and the alcohol removed under reduced pressure. The residueis distilled under reduced pressure to afford2-n-propyl-N,N-diethylaniline, B.P. 127-133 C./ 28 mm.

Other 2-alkyl-N,N-diethylanilines are prepared in the same way and havethe indicated properties: 2-isobuty1- N,N-diethylaniline, B.P. 124-127"C./ 25 mm.; 2-sec- 'butyl-N,N-diethylaniline, B.P. 129 C./25 mm.;2-nbutyl-N,N-diethylaniline, B.P. 143 C./29 mm.;2-isopropyl-N-N-diethylaniline, B.P. 126 C./ 28 mm. Use of formaldehydeor propionaldehyde in place of acetalde- 13 hyde affords thecorresponding N,N-dimethyl or N,N-di propyl aniline.

A different procedure is the following, as applied to making2-ethyl-N,N-diethylaniline.

A mixture of 100 g. of Z-ethylaniline and 150 g. of triethylphosphate isstirred and heated to about 160 C. When the exothermic reactionsubsides, the mixture is stirred and heated at 200 C. for 4 hours. Themixture is cooled and to it is carefully added a solution of 100 g. ofsodium hydroxide in 50 ml. of water. The mixture is stirred at roomtemperature for 12 hours. The precipitated oil is extracted into ether.The ether extracts are then dried, evaporated to dryness and the residuedistilled at atmospheric pressure. The fraction distilling at 220 C. is2-ethyl-N,N-diethylaniline.

(C) 74 g. of 2-n-propyl-N,N-diethylaniline is added, with stirring andcooling, to 400 ml. of sulfuric acid ((1. 1.84). The temperature duringthe above addition is held below 20 C. The solution is then cooled to C.and a solution of 20 ml. of nitric acid (d. 1.42) in 60ml. of sulfuricacid (d. 1.84) is added dropwise, keeping the temperature at 0 to 5 C.After the addition is complete the mixture is stirred at 5 C. for anadditional 30 minutes and then poured onto ice. The mixture isneutralized by the addition of solid sodium carbonate. Small amounts ofether are added during the addition to keep the foaming under control.After neutralization the mixture is brought to room temperature (todissolve the hydrated sodium sulfate) and extracted with 3 100 ml. ofether. The ether extracts are combined, washed with water, dried overmagnesium sulfate, filtered and concentrated to dryness. The residue isdistilled under reduced pressure to give 2n-propyl-S-nitro-'N,N-diethylaniline, B.P. 134 C./ 1.8 mm.

Other 2-alkyl-5-nitro-N,N-diloweralkylanilines are prepared in the sameWay from the appropriate starting material, representative examplesbeing: 2-is0butyl-5-niiro- N,N-diethylanil-ine, B.P. 134-l35 C./0.751.0mm. 2- sec butyl 5 nitro N,N, diethylaniline, B.P. 135 C./ 1.3 mm.;Z-n-butyl-S-nitro-N,N-diethylaniline, B.P. 143 C./ 1.65 mm.;2-isopropyl-5-nitro-N,N-diethylaniline, B.P. 124 C./ 1.45 mm.; and2-ethyl-5-nitro-N,N-diethylaniline, B.P. 126 C./0.5 mm.

The starting compounds for preparing the loweralkyl 6 dialkylamino 7loweralkyl 4 hydroxy quinoline- S-carboxylates of this invention(Examples 8-11) are 3- loweralkyl-4-d-iloweralkylamino anilines of theformula where Y is loweralkyl and Y is diloweralkylamino. They areobtained from the appropriate o-nitroalkylbenzene by (a) reacting saidsubstance with hydrogen and an aidehyde at superatmospheric pressure ina loweralkanol to produce 2-loweralkyl-N,N-diloweralkylaniline; (b)coupling said substance with the diazo salt of 2,5-dichloroaniline toproduce 3-loweralkyl-4-diloweralkylamino-2,S- dichloroazobenzene; and(c) decomposing the azobenzene with aluminum in ethanolic hydrogenchloride. Details of a representative preparation follow.

(D) A solution of 54 g. of 2-nitropropyl benzene in 500 ml. of methanoland 80 ml. of 37% formaldehyde is hydrogenated at room temperature at 40p.s.i. using 2 g. of 5% pallad ium-on-charcoal as the catalyst untilhydrogen uptake ceases. The catalyst is removed by filtration, and thefiltrate evaporated to dryness. The residue is distilled in vacuo togive 2-n-propyl-N,N-dimethylaniline. The correspondingN,N-diethylaniline and N,N-dipropylaniline are obtained by usingacetaldehyde or propionaldehyde in place of formaldehyde.

(E.) A solution composed of 16.2 g. of 2,5-dichloro aniline in 40 ml. ofconcentrated hydrochloric acid and 120 ml. of water is diazotized at 0C. using a solution of 7 g. of sodium nitrite in 30 ml. of water. Tothis solution, at 0 C., there is added a solution of 19.1 g. of2-n-propyl- N,N-diethy1aniline in 10 ml. of concentrated hydrochloricacid and 50 ml. of water. The solution is held at 0 C. and solidpotassium acetate added until the solution is acidic to litmus but notto Congo red paper. The mixture is then allowed to warm to roomtemperature and stirred for 14 hours. It is then extracted with 3X ml.of ether. The ether extracts are combined, Washed with water, sodiumbicarbonate solution, again with water, and then dried. The ethersolution is evaporated to dryness to give '8 g. of an oil. This oil isplaced on an alumina column and washed through with hexane. The hexaneis evaporated to give 5 g. of 3-n-propyl-4-diethylamino 2'5'- dichloroazobenzene.

3-n-propyl-4-dimethylamino-Z',5'-dichloro azobenzene,3-n-butyl-4-diethylamino-2',5'-dichloro azobenzene and other 3loweralkyl 4-diloweralkylamino-2',5'-dichloro azobenzenes are obtainedin like fashion.

(F) A total of 13 g. of 3-n-propyl 4-diethylamino-2 ,5'- dichloroazobenzene is dissolved in 30 ml. of ethanol, 40 ml. of concentratedhydrochloric acid and 40 m1. of water. The mixture is stirred vigorouslyat 6065 C. and aluminum powder is cautiously added. Cooling is necessaryto hold the temperature below 75 C. When the color of the solutionchanges from red to a greyish color, no more aluminum powder is addedbut 10 ml. of 'con centrated hydrochloric acid is added and the mixturestirred for two hours. This mixture is then steam distilled. About 1200ml. of distillate is collected and then the residue is made basic with50% sodium hydroxide. It is then steam distilled again. The first 800ml. of distillate is collected, and extracted with 3x 300 ml. of ether.The ether extracts are combined and concentrated to dryness to give 5.7g. of 3-n-propyl-4-diethylamino-aniline.

Other starting materials such as 3-n-propyl-4-di-methylamino-aniline and3-n-butyl-4-diethylamino aniline are obtained in like manner from theappropriate azobenzene.

The starting compounds for making the loweralkyl 6,7bis-diloweralkylamino 4-hydroxy-quinoline-3-carboxylates of theinvention are 3,4-bis-diloweralkylamino anilines, the preferredsynthesis of which depends upon the particular diloweralkylaminoradical. 3,4-bis-dimethylamino aniline is prepared by catalytichydrogenation of 3,4-bis-dimethylamino-nitrobenzene in methanol overpalladium-on-charcoal catalyst.

In order to obtain such 3,4-disubstituted anilines Where one or both ofthe dialkylamino substituents are other than dimethylamino, thefollowing preparative method is preferred: 2-fluoroaniline is reactedwith a triloweralkyl phosphate to give 2-fluoro-N,N-diloweralkylaniline;this material is nitrated with nitric acid-sulfuric acid to form3-dialkylamino-4-fluoro-nitrobenzene, which substance is then treatedwith a diloweralkylamine in aqueous alcohol to yield3,4-bis-dialkylamino-nitrobenzene, where the two dialkylamino radicalsmay be the same or different; this nitrobenzene is catalyticallyhydrogenated with palladium catalyst to give 3,4-diloweralkylaminoaniline. Details are as follows:

(G) A mixture of g. of 2-fluoroaniline and g. of triethylphosphate isstirred and heated to about C. where there is a slight exothermicreaction. When this subsides heating is applied again and there isanother exotherm at about C. The mixture is then heated at 203 C.(internal temperature) for 4 hours. The mixture is cooled to roomtemperature and a solution of 100 g. of sodium hydroxide in 400 ml. ofwater is added in portions with stirring. The mixture is stirred for 12hours.

Another 500 ml. of Water is then added and the resulting oil extractedwith 3X 100 ml. of ether. The combined ether extracts are washed oncewith water, dried, and evaporated to dryness. The residue is distilledat atmospheric pressure, and 2-fluoro-N,N-diethyl aniline distills as acolorless oil at 198 C. When this experiment 15 is repeated usingtrimethyl phosphate or tributyl phosphate, there is obtained2-fluoro-N,N-dimethyl aniline and 2-fiuoro-N,N-dibutyl aniline,respectively.

(H) To a solution of 60 g. of 2-i'luoro-N,N-diethyl aniline in 500 ml.of concentrated sulfuric acid, cooled to about 18 C., there is added asolution of 24.6 g. (16.2 ml.) of fuming nitric acid in 150 ml. ofconcentrated sulfuric acid over 1 hour, keeping the temperature below 19C. The solution is then held at room temperature for 2 hours, thenpoured onto ice. The solution is neutralized with ammonium hydroxidewith cooling. An oil precipitates which is extracted with 3X 200 m1. ofether and the combined ether extracts are washed with 3 X 150 'ml. ofwater, the ether solution dried and then evaporated to dryness. Theresidue is distilled at about 0.5 mm./Hg. A small forerun of 1.5 g.boiling at 65-80" C. is discarded. The second and main fraction distillsat 98 C. as an orange oil. It is substantially pure 3-diethylamino-4-fluoro-nitrobenzene.

3-dimethylamino-4-fluoro-nitrobenzene and3-dibutylamino-4-fluoro-nitrobenzene are obtained in a similar fashionfrom the corresponding 2-fiuoro-N,N-dialkyl aniline.

(I) A mixture of 21.2 g. of 3-diethylamino-4-fluoronitro-benzene, 60 g.of diethylammine and 50 ml. of 50% ethanol is heated in a bomb at 155 C.for 11 hours. Most of the solvent and excess diethylamine is removed invacuo. The residue is taken up in 50 ml of 1:1 waterether. The etherlayer is separated, washed twice with water, dried and then evaporatedto a red oil. This oil is distilled at about 0.5 mm./ Hg.3,4-bis-diethylaminonitrobenzene distills as a red oil at 140442 C. 0.5mm.

When 3-dimethylamino-4-fiuoro-nitrobenzene or3-dibutylamino-4-fluoro-nitrobenzene are treated with diethylamine bythe above procedure there is obtained3-dimethylamino-4-diethylamino-nitrobenzene and3-dibutylamino-4-diethylamino-nitrobenzene, respectively.

Alternatively, the compounds may be made from 2- chloroaniline, asfollows:

(I) A mixture of 60 g. of 2-chloroani1ine and 90 g. of triethylphosphate is stirred and heated to 200 C. for 3.5 hours. The mixture iscooled to room temperature and a solution of 65 g. of sodium hydroxidein 300 ml. of water added. After stirring for 2 hours the precipitatedoil is extracted with ether. The ether extracts are dried, evaporated todryness, and the residue distilled at 15 mm. 2-chloro-N,N-diethylanilinedistills at 9294 C.

(K) A solution of 4.5 g. of fuming nitric acid in 15 ml. of concentratedsulfuric acid is added over 20 minutes to g. of2-chloro-N,N-diethylaniline in 50 ml. of concentrated sulfuric acidkeeping the temperature between to C. The solution is then poured ontoice and neutralized with concentrated ammonium hydroxide. The oil isextracted with ether, the ether extract washed with water, dried, thenevaporated to dryness. The residue is distilled at 1 mm.;3-diethylamino-4-chloro-nitrobenzene distills at 120-123 C.

(L) A mixture of 8 g. of 3-diethylarnino-4-chlorornitrobenzene, ml. of40% aqueous dimethylamine, and 10 ml. of ethanol is heated in a bomb atC. for 12 hours. The reaction mixture is concentrated in vacuo and theresidue was taken up between ether and water. The ether is separated,washed with water, dried, then evaporated to dryness in vacuo. Theresidue is dissolved in a little petroleum ether then cooled in Dry Iceacetone. 3-diethylamino-4-dimethylamino-nitrobenzene crystallizes, MP.4850 C.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

What is claimed is:

1. A compound having the structural formula R5 COOR;

where R is loweralkyl; R and R each are loweralkyl of 2-4 carbon atomsor diloweralkylamino, at least one of R and R being diloweralkylamino.

2. A compound of claim 1 wherein R represents methyl or ethyl.

3. The compound of claim 1 which is methyl6-npropyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate.

4. The compound of claim 1 which is ethyl 6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate.

5. The compound of claim 1 which is methyl 6-n-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate.

6. The compound of claim 1 which is methyl6,7-bisdiethylarnino-4-hydroxy-quinoline-3-carboxylate.

7. The compound of claim 1 which is methyl 6-diethy1-amino-7-n-propyl-4-hydroxy-quinoline-3-carboxylate.

8. The quaternary salt of a compound having the formula Re C O O R;

where R represents loweralkyl; R and R; each represent loweralkyl of 24carbon atoms or diloweralkylamino, at least one of R and R beingdiloweralkylamino, and a lower alkyl halide.

References Cited UNITED STATES PATENTS 3,316,147 4/1967 Watson 16753.1

ALEX MAZEL, Primary Examiner.

D. DAUS, Assistant Examiner.

